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DNA binding to TLR9 expressed by red blood cells promotes innate immune activation and anemia.
Lam, L K Metthew; Murphy, Sophia; Kokkinaki, Dimitra; Venosa, Alessandro; Sherrill-Mix, Scott; Casu, Carla; Rivella, Stefano; Weiner, Aaron; Park, Jeongho; Shin, Sunny; Vaughan, Andrew E; Hahn, Beatrice H; Odom John, Audrey R; Meyer, Nuala J; Hunter, Christopher A; Worthen, G Scott; Mangalmurti, Nilam S.
  • Lam LKM; Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Murphy S; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Kokkinaki D; Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Venosa A; Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Sherrill-Mix S; Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112, USA.
  • Casu C; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Rivella S; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Weiner A; Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Park J; Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • Shin S; Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA.
  • Vaughan AE; Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA.
  • Hahn BH; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Odom John AR; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Meyer NJ; Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA.
  • Hunter CA; Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Worthen GS; Department of Microbiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Mangalmurti NS; Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Sci Transl Med ; 13(616): eabj1008, 2021 Oct 20.
Article in English | MEDLINE | ID: covidwho-1518118
ABSTRACT
Red blood cells (RBCs) are essential for aerobic respiration through delivery of oxygen to distant tissues. However, RBCs are currently considered immunologically inert, and few, if any, secondary functions of RBCs have been identified. Here, we showed that RBCs serve as critical immune sensors through surface expression of the nucleic acid­sensing Toll-like receptor 9 (TLR9). Mammalian RBCs expressed TLR9 on their surface and bound CpG-containing DNA derived from bacteria, plasmodia, and mitochondria. RBC-bound mitochondrial DNA was increased during human and murine sepsis and pneumonia. In vivo, CpG-carrying RBCs drove accelerated erythrophagocytosis and innate immune activation characterized by increased interferon signaling. Erythroid-specific deletion of TLR9 abrogated erythrophagocytosis and decreased local and systemic cytokine production during CpG-induced inflammation and polymicrobial sepsis. Thus, detection and capture of nucleic acid by TLR9-expressing RBCs regulated red cell clearance and inflammatory cytokine production, demonstrating that RBCs function as immune sentinels during pathologic states. Consistent with these findings, RBC-bound mitochondrial DNA was elevated in individuals with viral pneumonia and sepsis secondary to coronavirus disease 2019 (COVID-19) and associated with anemia and severity of disease. These findings uncover a previously unappreciated role of RBCs as critical players in inflammation distinct from their function in gas transport.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Toll-Like Receptor 9 / Immunity, Innate / Anemia Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Sci Transl Med Journal subject: Science / Medicine Year: 2021 Document Type: Article Affiliation country: Scitranslmed.abj1008

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Toll-Like Receptor 9 / Immunity, Innate / Anemia Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Sci Transl Med Journal subject: Science / Medicine Year: 2021 Document Type: Article Affiliation country: Scitranslmed.abj1008